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    How GLP-1 drugs work

    GLP-1 drugs copy a gut hormone that raises insulin, lowers glucagon, slows the stomach and curbs appetite.[1] Engineering made them last a week per dose, and newer molecules also act on the GIP, glucagon or amylin systems.[2][3][4]

    Editor reviewedStrict sourcingUpdated GLP-1 and metabolic medicineHealth and medicineLife sciences

    GLP-1 drugs work by copying a hormone the gut already makes after meals. Understanding that hormone explains both why the drugs work and why they cause stomach side effects.[1][5]

    The incretin hormones

    When you eat, cells in the gut lining release a hormone called GLP-1 (glucagon-like peptide-1). It tells the pancreas to release more insulin and less glucagon. It also slows how fast the stomach empties and makes people eat less.[1] Its insulin effect depends on blood sugar: it is strongest when sugar is high.[6] GLP-1 and a sister hormone, GIP, are called “incretins” because they boost insulin after a meal.[7]

    GLP-1 is secreted by enteroendocrine cells. Through the GLP-1 receptor it augments glucose-stimulated insulin secretion, inhibits glucagon, delays gastric emptying and reduces food intake.[1] Reviews also describe effects on natriuresis, inflammation, reward behaviour and palatability, though not all of these are established in humans.[6] The physiologically active peptide, GLP-1 (7-37), was identified in 1987 by Habener and Mojsov. That work was recognised with the 2024 Lasker~DeBakey Clinical Medical Research Award.[8]

    Making a hormone into a drug

    To work as a medicine, the hormone had to last far longer in the body. Novo Nordisk scientists built liraglutide and then semaglutide, whose half-life was extended about two-thousand-fold, so it works as one injection a week. It was approved for diabetes in 2017 and for weight loss in 2021.[2]

    Drug designers protected the peptide from degradation and slowed its clearance. Semaglutide’s half-life extension of about 2,000-fold supports once-weekly subcutaneous dosing.[2] The same goals drove work on orally bioavailable agonists, allosteric modulators and unimolecular multi-agonists.[9] Oral peptide semaglutide 25 mg must be taken in the morning at least 30 minutes before food. The non-peptide orforglipron has no food or water restrictions.[10][11]

    One molecule, several receptors

    The newest drugs are single molecules that act on more than one hormone receptor. tirzepatide activates the GLP-1 and GIP receptors.[7] retatrutide, still in testing, adds the glucagon receptor.[3] cagrisema takes a different route: it combines semaglutide with cagrilintide, a long-acting copy of the hormone amylin.[4]

    Multi-agonism has raised average weight loss in trials. SURMOUNT-1 reported -20.9% with tirzepatide 15 mg at 72 weeks.[12] TRIUMPH-1 reported -25.0% with retatrutide 12 mg at 80 weeks by intention-to-treat, versus -3.9% on placebo (Lilly’s topline efficacy-estimand figure was 28.3%).[13] Survodutide, which pairs GLP-1 with glucagon receptor agonism, produced -9.8% versus -3.9% at 76 weeks in people with obesity and type 2 diabetes.[14] The pharmacology is not settled. Amgen’s MariTide pairs GLP-1 receptor agonism with GIP receptor antagonism, the opposite GIP strategy to tirzepatide, and also produced double-digit weight loss in phase 2.[15]

    Side effects follow from the mechanism

    The most common adverse events in the main trials were gastrointestinal, such as nausea, diarrhoea, constipation and vomiting. They were usually mild to moderate.[5][16] Discontinuation because of adverse events was higher on drug than on placebo: 16.6% versus 8.2% in SELECT, and 11.3% versus 4.9% at the top retatrutide dose in TRIUMPH-1.[17][16] Rarer risks are also tracked. In 2025 the EMA listed a form of sudden vision loss (NAION) as a very rare side effect of semaglutide.[18]

    Questions readers ask

    Why do GLP-1 drugs cause weight loss and not just lower blood sugar?

    GLP-1 slows stomach emptying and reduces food intake as well as raising insulin and suppressing glucagon. Long-acting drugs keep these effects going.[1]

    Why don't GLP-1 drugs cause low blood sugar on their own?

    GLP-1 stimulates insulin release in a glucose-dependent way, so the effect is strongest when blood sugar is high.[6]

    What is the difference between semaglutide, tirzepatide and retatrutide?

    Semaglutide acts on the GLP-1 receptor. Tirzepatide activates both GIP and GLP-1 receptors. Retatrutide, which is still investigational, activates GIP, GLP-1 and glucagon receptors.[7][3]

    Who discovered GLP-1?

    Joel Habener and Svetlana Mojsov identified the active form, GLP-1 (7-37), in 1987. They shared the 2024 Lasker award with Novo Nordisk's Lotte Bjerre Knudsen, who led development of liraglutide and semaglutide.[8][2]

    Sources

    Each numbered claim is a statement we checked against the sources listed with it. Status shows how well established it is.

    1. [1]

      GLP-1 is a hormone released from gut enteroendocrine cells that augments insulin secretion, inhibits glucagon secretion, slows gastric emptying and reduces food intake. confirmedas of 2026-10-10

    2. [2]

      Novo Nordisk scientists developed liraglutide and then semaglutide, whose half-life was extended about two-thousand-fold, allowing once-weekly injection; semaglutide was approved in the US for diabetes in 2017 and for weight loss in 2021. confirmedas of 2026-10-10

    3. [3]

      Retatrutide is an investigational agonist of three receptors, GIP, GLP-1 and glucagon. confirmedas of 2026-10-10

    4. [4]

      CagriSema is a fixed-dose combination of cagrilintide 2.4 mg, a long-acting amylin analogue, and semaglutide 2.4 mg. confirmedas of 2026-10-10

    5. [5]

      In ATTAIN-1, adverse events led to treatment discontinuation in 5.3% to 10.3% of orforglipron groups versus 2.7% on placebo, mostly from gastrointestinal effects. confirmedas of 2025-09-16

    6. [6]

      GLP-1 stimulates insulin secretion in a glucose-dependent way, reviews describe further effects including natriuresis, reduced inflammation and effects on reward behaviour, and its receptor agonists are modified for enhanced potency and sustained action. confirmedas of 2026-10-10

    7. [7]

      Tirzepatide is a single molecule that activates both the GIP and GLP-1 receptors. confirmedas of 2026-10-10

    8. [8]

      Joel Habener and Svetlana Mojsov identified GLP-1 (7-37) as the physiologically active form of the hormone in 1987, work recognised with the 2024 Lasker~DeBakey Clinical Medical Research Award shared with Novo Nordisk scientist Lotte Bjerre Knudsen. confirmedas of 2026-10-10

    9. [9]

      Efforts to refine GLP-1 therapies have driven development of orally available agonists, allosteric modulators and single molecules that act on several receptors (multi-agonists). confirmedas of 2026-10-10

    10. [10]

      Foundayo can be taken at any time of day without food or water restrictions, whereas the Wegovy pill must be taken in the morning at least 30 minutes before food or drinks other than water. confirmedas of 2026-04-01

    11. [11]

      Orforglipron is a small-molecule, non-peptide GLP-1 receptor agonist taken by mouth once daily. confirmedas of 2026-10-10

    12. [12]

      In SURMOUNT-1, which enrolled 2,539 adults with obesity or overweight and no diabetes, weekly tirzepatide produced mean weight changes of -15.0%, -19.5% and -20.9% at doses of 5, 10 and 15 mg at 72 weeks, versus -3.1% with placebo. confirmedas of 2022-06-04

    13. [13]

      The peer-reviewed TRIUMPH-1 report (NEJM, 29 September 2026) gave mean weight changes at 80 weeks of -17.6%, -23.7% and -25.0% with retatrutide 4, 9 and 12 mg versus -3.9% with placebo under the treatment-regimen (intention-to-treat) estimand; Lilly's May topline figures of 19.0%, 25.9% and 28.3% used the efficacy estimand. confirmedas of 2026-09-29

    14. [14]

      In the phase 3 SYNCHRONIZE-2 trial of 752 adults with obesity and type 2 diabetes, Boehringer Ingelheim's glucagon/GLP-1 dual agonist survodutide produced mean weight changes of -8.2% and -9.8% at 76 weeks versus -3.9% with placebo. confirmedas of 2026-10-01

    15. [15]

      Amgen's maridebart cafraglutide (MariTide), a monthly peptide-antibody conjugate that activates the GLP-1 receptor and blocks the GIP receptor, produced mean weight loss of 12.3% to 16.2% at 52 weeks versus 2.5% with placebo in a phase 2 obesity trial. confirmedas of 2026-10-10

    16. [16]

      In TRIUMPH-1, discontinuation due to adverse events was 11.3% at the 12 mg retatrutide dose versus 4.9% with placebo; the most common adverse events were gastrointestinal. confirmedas of 2026-05-21

    17. [17]

      In SELECT, adverse events led to permanent discontinuation in 16.6% of semaglutide patients versus 8.2% on placebo. confirmedas of 2023-11-11

    18. [18]

      In June 2025 the EMA's safety committee recommended listing NAION, a form of sudden vision loss, as a very rare side effect of semaglutide medicines, affecting up to 1 in 10,000 people. confirmedas of 2025-06-06

    Revision history (2)
    1. Page created.
    2. Refresh: updated retatrutide figures to the peer-reviewed TRIUMPH-1 result and added survodutide phase 3 data.

    Created Oct 10, 2026. Last reviewed by an editor on Oct 10, 2026. Next scheduled review: Jan 10, 2027.

    Cite this page

    "How GLP-1 drugs work." ContentLora, updated Oct 10, 2026. https://contentlora.com/explain/how-glp-1-drugs-work

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